Saturday, 22 October 2016

An argument against statin use for GBM

A new study by a joint team from UCLA, UCSD etc. has important implications for the use of statins as a repurposed GBM therapy.   The study shows that statins were selectively toxic to Normal Human Astrocytes, and relatively ineffective against two GBM cell lines (U87EGFRvIII, and GBM39 - a patient derived line with EGFR amplification and EGFRvIII expression).


This can be understood by the fact that normal astrocytes rely on de novo cholesterol synthesis, while GBM cells have much less reliance on cholesterol synthesis, but instead import cholesterol from the brain environment via low density lipoprotein receptors (LDLR), in a parasitic manner.  The study showed that GBM clinical samples have increased expression of LDLR and suppressed levels of enzymes involved in cholesterol synthesis.

A different strategy was found to be far more effective, which involved an experimental drug called LXR-623, an LXR-beta agonist.   In an orthotopic GBM mouse model this drug extended mouse survival significantly without toxicity in the healthy brain.  By stimulating LXR-beta, the drug suppresses LDL uptake into cells and increases cholesterol efflux from the cell, selectively depriving the GBM cells of cholesterol.  The drug is brain-penetrant and has already been in phase 1 safety and pharmacokinetic/pharmacodyamic trial with healthy volunteers.

As a non-approved drug, LXR-623 is not generally available to patients, but we hope to see a trial for GBM initiated based on this excellent preclinical work.

Study abstract:  An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers  (full study will be uploaded to the Library, folder 2)

4 comments:

  1. I certainly agree that LXR-623 looks promising. Depriving glioma cells of cholesterol seems to be a promising strategy.

    I think this research shouldn't be interpreted as an argument against statins--I see the opposite.

    Relative cytotoxicity of lovastatin in cell culture systems is, I think, a red herring. In actual human use, statins have been used widely since the mid 1980s, for millions of patient-years. Some have raised questions about long-term brain effects, but other evidence suggests benefits in e.g., delaying progression of Alzheimer's and other neurodegenerative disorders. We're not seeing any big problem with normal brains being harmed by statins.

    The evidence seems to show glioma cells are especially dependent on circulating LDL-cholesterol to function, whereas normal brain cells are not. Statins are highly effective in lowering LDL-cholesterol safely. That is, in whole organisms, one might expect statins to be useful, by precisely the mechanisms elucidated here. This mechanism of potential benefit cannot be demonstrated in cell culture systems, only whole animals or humans would be suitable for evaluating this mechanism.

    Epidemiological evidence seems to support an inverse relationship between statin use and risk og glioma.

    But even in just cell cultures, there's more to statins than just hoped-for cytotoxicity. See, for example,
    https://www.ncbi.nlm.nih.gov/pubmed/25497898
    Lovastatin and perillyl alcohol inhibit glioma cell invasion, migration, and proliferation--impact of Ras-/Rho-prenylation.

    Also relevant to evaluating the potential utility of statins in glioma:

    https://www.ncbi.nlm.nih.gov/pubmed/20044596
    HMG-CoA reductase inhibition causes increased necrosis and apoptosis in an in vivo mouse glioblastoma multiforme model.
    (where low statin dose is superior to high dose or control)

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    Replies
    1. This is great Steve, constructive and respectful criticism is always welcome.

      As far as lovastatin toxicity to normal brain, point taken. The concentrations used in the study (1-5 uM) are not actually achievable in the blood let alone the nervous system. In one pharmacokinetic study I looked at, Cmax after repeated doses of lovastatin was only 8.5 ug/L (which translates to 21 nM or 0.021 uM). Plamsa protein binding is at least 95% according to Drugbank, leaving very low nanomolar levels of free compound in the plasma, even at Cmax.

      So yes I'd agree that concentrations of the drug reaching the plasma are not actually cytotoxic, to healthy cells or cancer cells, but of course higher levels of the drug might accumulate in specific organs.

      I can't yet agree with your statement: "The evidence seems to show glioma cells are especially dependent on circulating LDL-cholesterol to function, whereas normal brain cells are not."

      A quote from the study itself seems to counter that. This comes from the introduction:

      "The brain, for instance, is the most
      cholesterol-rich organ of the body, containing approximately
      20% of total body cholesterol (Dietschy, 2009). However, the
      brain cholesterol pool is virtually separate from cholesterol
      metabolism in the periphery. Because cholesterol cannot be
      transported across the blood-brain barrier into the CNS, almost
      all brain cholesterol is synthesized de novo"

      If this statement is true, it would imply that levels of circulating LDL make no difference as far as glioma therapy, since virtually all the cholesterol in the brain is synthesized de novo in the brain rather than taken up from the systemic circulation. It someone can prove that statement to be false, I'm willing to listen.

      I'm aware of the epidemiological evidence, but a single study is not usually enough to convince me. The conclusions often vary from study to study. If a number of studies concluded the same thing it would be more convincing.

      I've also aware of the animal study you referenced. In spite of the increased necrosis in the simvastatin treated animals, survival was not significantly prolonged. "Simvastatin did not provide an overall advantage in survival, tumor size or vascular density". This is not a good sign in an animal model, as mouse models often show exaggerated effects, and even studies showing pronounced survival benefits in mice often don't translate to humans.

      I remain open to the possibility that statins may be helpful as a glioma therapy. There are arguments for and against. I still feel the study in question is an argument against, based on the finding that clinical glioma samples have greatly suppressed levels of cholesterol biosynthetic enzymes, INCLUDING HMG-CoA reductase, which is the actual target of statins. Lowering circulating LDL is not likely to help, if it's true that glioma cells are simply parasitizing cholesterol produced locally.

      I'd be ready to change my opinion if any truly compelling evidence came into light. Likewise I wouldn't tell any GBM patient not to take statins. There's still the possibility of benefit. My bottom line is that I feel there are many drugs with superior evidence, including superior mouse evidence, and that one needs to prioritize based on current evidence. I also grant that everyone's standard of what constitutes convincing evidence will be different.

      Again, thanks for your comments Steve. I always look forward to reading yours.

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    2. Thanks. You're probably right on all counts. I simply assumed that if glioma cells are deficient in synthesis of cholesterol, they were reliant on bloodstream source. The existence of the blood-brain barrier affects brain physiology in myriad ways. I have more reading to do. ;-)

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  2. For what it's worth, one vitro study found that a 5 uM concentration of atorvastatin was actually counterproductive in cells with oncogenic IDH1 mutations, leading to increased production of the oncometabolite 2-hydroxyglutarate (2-HG). The relevance of this is uncertain though given achievable levels of atorvastatin in the blood plasma is in the low nanomolar range.

    https://www.ncbi.nlm.nih.gov/pubmed/27354064

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